Quinuclidine-substituted hetero-bicyclic aromatic compounds for the treatment of disease

Abstract

The invention provides compounds of Formula I: wherein W 0 is a bicyclic moiety and is These compounds may be in the form of pharmaceutical salts or compositions, may be in pure enantiomeric form or racemic mixtures, and are useful to treat diseases or conditions in which α7 is known to be involved.

1 - 98 . (canceled)  
     
     
         99 . A method for treating a disease or condition in a mammal in need thereof, wherein the α7 nicotinic acetylcholine receptor is implicated comprising administering to the mammal a therapeutically effective amount of compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein W 0  is a bicyclic moiety and is  
       
         
           
           
               
               
           
         
         X is O, or S;  
         R 1  is H, alkyl, cycloalkyl, halogenated alkyl, substituted phenyl, or substituted naphthyl;  
         R 2  is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, or aryl;  
         R 3  is H, F, alkyl, halogenated alkyl, substituted alkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy, R 7 , R 9 , —N(R 4 )-aryl, —O-substituted phenyl, —O-substituted naphthyl, —S-substituted phenyl, —S-substituted naphthyl, alkyl substituted on the ω carbon with naphthyl, or alkyl substituted on the ω carbon with substituted naphthyl;  
         W is C(H) where  
         V—Z—Y is selected from O—C(R 3 )═N, O—C(R 5 )(R 3 )—N(R 4 ), O—C(R 5 )(R 3 )—S, O—N═C(R 5 ), O—C(R 3 )(R 5 )—O, S—C(R 3 )═N, S—C(R 5 )(R 3 )—N(R 4 ), S—N═C(R 5 ), N═C(R 3 )—O, N═C(R 3 )—S, N═C(R 3 )—N(R 4 ), N(R 4 )—N═C(R 5 ), N(R 4 )—C(R 5 )(R 3 )—O, N(R 4 )—C(R 5 )(R 3 )—S, N(R 4 )—C(R 5 )(R 3 )—N(R 4 ), C(R 5 ) 2 —O—N(R 4 ), C(R 5 ) 2 —N(R 4 )—O, C(R 5 ) 2 —N(R 4 )—S, C(R 5 )═N—O, C(R 5 )═N—S, C(R 5 )═N—N(R 4 ), C(R 5 ) 2 —O—C(R 5 ) 2 , C(R 5 ) 2 —S—C(R 5 ) 2 , C(R 5 ) 2 —N(R 4 )—C(R 5 ) 2 , or C(R 5 ) 2 —C(R 3 )(R 5 )—C(R 5 ) 2 ;  
         Q is N(R 19 ), O, or S;  
         W is N where  
         V—Z—Y is selected from O—C(R 3 )═N, O—C(R 5 )(R 3 )—N(R 4 ), O—C(R 5 )(R 3 )—S, O—N═C(R 5 ) O—C(R 3 )(R 5 )—O, S—C(R 3 )═N, S—C(R 5 )(R 3 )—N(R 4 ), S—N═C(R 5 ), N═C(R 3 )—O, N═C(R 3 )—S, N═C(R 3 )—N(R 4 ), N(R 4 )—N═C(R 5 ), N(R 4 )—C(R 5 )(R 3 )—O, N(R 4 )—C(R 5 )(R 3 )—S, N(R 4 )—C(R 5 )(R 3 )—N(R 4 ), C(R 5 ) 2 —O—N(R 4 ), C(R 5 ) 2 —N(R 4 )—O, C(R 5 ) 2 —N(R 4 )—S, C(R 5 )═N—O, C(R 5 )═N—S, C(R 5 )═N—N(R 4 ), C(R 5 )═C(R 3 )—C(R 5 ) 2 , or C(R 5 ) 2 —C(R 3 )(R 5 )—C(R 5 ) 2 ;  
         R 4  is H, or alkyl;  
         R 5  is H, F, Br, Cl, I, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, —CN, —NO 2 , —OR 1 , —C(O)NH 2 , —C(O)N(R 16 ) 2 , —NHR 1 , —NR 1 COR 16 , —N(R 10 ) 2 , —SR 1 , —C(O)R 16 , —CO 2 R 1 , aryl, R 7 , or R 9 ;  
         R 6  is H, F, Cl, Br, I, —CN, —CF 3 , —OR 16 , —SR 16 , or —N(R 16 ) 2 ;  
         R 7  is 5-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms independently selected from the group consisting of —O—, ═N—, —N(R 19 )—, and —S—, and having 0-1 substituent selected from R 20  and further having 0-3 substituents independently selected from F, Cl, Br, or I, or R 7  is 9-membered fused-ring moieties having a 6-membered ring fused to a 5-membered ring and having the formula  
         
           
             
             
                 
                 
             
           
         
         wherein E is O, S, or NR 19 ,  
         
           
             
             
                 
                 
             
           
         
         wherein E and G are independently selected from CR 18 , O, S, N, or NR 19 , and A is CR 18  or N, or  
         
           
             
             
                 
                 
             
           
         
         wherein E and G are independently selected from CR 18 , O, S, N, or NR 19 , and A is CR 18  or N, each 9-membered fused-ring moiety having 0-1 substituent selected from R 20  and further having 0-3 substituent(s) independently selected from F, Cl, Br, or I, and having a bond directly or indirectly attached to the core molecule where valency allows in either the 6-membered or the 5-membered ring of the fused-ring moiety;  
         Each R 8  is independently F, Br, Cl, I, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, —CN, —CF 3 , —OR 1 , —C(O)NH 2 , —NHR 1 , —SR 1 , —CO 2 R 1 , aryl, phenoxy, substituted phenoxy, heteroaryl, —N(R 4 )-aryl, or —O-substituted aryl.  
         R 9  is 6-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms selected from ═N— and having 0-1 substituent selected from R 20  and 0-3 substituent(s) independently selected from F, Cl, Br, or I, or R 9  is 10-membered heteroaromatic bi-cyclic moieties containing within one or both rings 1-3 heteroatoms selected from ═N—, including, but not limited to, quinolinyl or isoquinolinyl, each 10-membered fused-ring moiety having 0-1 substituent selected from R 20  and 0-3 substituent(s) independently selected from F, Cl, Br, or I and having a bond directly or indirectly attached to the core molecule where valency allows;  
         Each R 10  is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from R 13 , cycloalkyl substituted with 1 substituent selected from R 13 , heterocycloalkyl substituted with 1 substituent selected from R 13 , halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl, or substituted phenyl;  
         Each R 11  is independently H, alkyl, cycloalkyl, heterocyclo-alkyl, halogenated alkyl, halogenated cycloalkyl, or halogenated heterocycloalkyl;  
         R 13  is —OR 11 , —SR 11 , —NR 11 R 11 , —C(O)R 11 , —C(O)NR 11 R 11 , —CN, —CF 3 , —NR 11 C(O)R 11 , —S(O) 2 NR 11 R 11 , —NR 11 S(O) 2 R 11 , or —NO 2 ;  
         R 16  is H, alkyl, substituted alkyl, cycloalkyl, halogenated alkyl, heterocycloalkyl, substituted heterocycloalkyl, substituted phenyl, or substituted naphthyl;  
         Each R 18  is independently selected from H, F, Cl, Br, I, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, —OR 11 , —SR 11 , —NR 11 R 11 , —C(O)R 11 , —NO 2 , —C(O)NR 11 R 11 , —CN, —NR 11 C(O)R 11 , —S(O) 2 NR 11 R 11 , or —NR 11 S(O) 2 R 11 , or a bond directly or in-directly attached to the core molecule, provided that there is only one said bond to the core molecule within the 9-membered fused-ring moiety, further provided that the fused-ring moiety has 0-1 substituent selected from alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, —OR 11 , —SR 11 , —NR 11 R 11 , —C(O)R 11 , —NO 2 , —C(O)NR 11 R 11 , —CN, —NR 11 C(O)R 11 , —S(O) 2 NR 11 R 11 , or —NR 11 S(O) 2 R 11 , and further provided that the fused-ring moiety has 0-3 substituent(s) selected from F, Cl, Br, or I;  
         R 19  is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, phenyl, or phenyl having 1 substituent selected from R 20  and further having 0-3 substituents independently selected from F, Cl, Br, or I;  
         R 20  is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, —OR, 11 , —SR 11 , —NR 11 R 11 , —C(O)R 11 , —C(O)NR 11 R 11 , —CN, —NR 11 C(O)R 11 , —S(O) 2 NR 11 R 11 , —NR 11 S(O) 2 R, 11 , —NO 2 , alkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or R 13 , cycloalkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or R 13 , or heterocycloalkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or R 13 ;  
         or pharmaceutically acceptable salt, or racemic mixture thereof;  
         wherein the disease or condition is psychosis, attention deficit disorder, attention deficit hyperactivity disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, depression, general anxiety disorder, age-related macular degeneration, Parkinson's disease, tardive dyskinesia, Pick's disease, post traumatic stress disorder, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.  
       
     
     
         100 . The method of  claim 99 , wherein X is O, and R 1  is H.  
     
     
         101 . The method of  claim 100 , wherein R 2  is H, alkyl, substituted alkyl, halogenated alkyl, or cycloalkyl.  
     
     
         102 . The method of  claim 101 , wherein W 0  includes 1,3-benzoxazol-6-yl, 1,3-benzoxazol-5-yl, 1,3-benzothiazol-6-yl, indan-5-yl, 1,3-benzodioxol-5-yl, [1,3]oxazolo[5,4-c]pyridin-6-yl, 2-benzoisothiophen-5-yl, 1,3-benzothiazol-5-yl 1,2-benzisoxazol-6-yl, 1,2-benzisoxazol-5-yl, or 1H-indazol-6-yl, optionally substituted with F, Br, Cl, alkyl, halogenated alkyl, substituted alky, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy, —CF 3 , —CN, —NO 2 , —OR 1 , —NHR 1 , —N(R 10 ) 2 , —N(R 4 )-aryl, —SR 1 , —C(O)N(R 16 ) 2 , or —NR 1 COR 16 .  
     
     
         103 . The method of  claim 102 , wherein the compound of Formula I has the R stereochemistry at C3 of quinuclidine.  
     
     
         104 . The method of  claim 103 , wherein the compound of Formula I includes N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-6-carboxamide; N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-6-carboxamide; N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-5-carboxamide; N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-5-carboxamide; N-((3R)1-azabicyclo [2.2.2]oct-3-yl)-1,3-benzothiazole-6-carboxamide; N-((3R)1-azabicyclo[2.2.2]oct-3-yl)indane-5-carboxamide; N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzodioxole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[5,4-c]pyridine-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-benzoisothiophene-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-6-carboxamide; N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-6-carboxamide; N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-6-carboxamide; N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-5-carboxamide; N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-5-carboxamide; N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzothiazole-6-carboxamide; N-((2S ,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)indane-5-carboxamide; N-((2S,3R)-2-methyl-1-azabicyclo [2.2.2]oct-3-yl)-1,3-benzodioxole-5-carboxamide; N-[(2S ,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[5,4-c]pyridine-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-benzoisothiophene-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo [2.2.2]oct-3-yl]-1,3-benzothiazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-6-carboxamide; or a pharmaceutically acceptable salt thereof.  
     
     
         105 . The method of  claim 103 , wherein the compound of Formula I includes N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1H-indazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1H-indazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1H-indazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1H-indazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]- I,2-benzisothiazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1,2-benzisothiazole-6-carboxamide; N-[(3R)-1-azabicyclo [2.2.2]oct-3-yl]-3-ethyl-1,2-benzisothiazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisothiazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisothiazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzoxazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzoxazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzothiazole-6-carboxamide; 
 N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzothiazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1,3-benzothiazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1,3-benzothiazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-ethyl-1,3-benzothiazole-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-ethyl-1,3-benzothiazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1,3-benzodioxole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-ethyl-1,3-benzodioxole-5-carboxamide; N-[(3R)-1-azabicyclo [2.2.2]oct-3-yl]-2,2-dimethyl-1,3-benzodioxole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-benzofuran-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2H-isoindole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-benzimidazole-5-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]thiazolo[5,4-c]pyridine-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]thiazolo[4,5-c]pyridine-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]dioxolo[4,5-c]pyridine-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[4,5-c]pyridine-6-carboxamide; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-imidazo[4,5-c]pyridine-6-carboxamide;    N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1H-indazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1H-indazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1H-indazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1H-indazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]—1,2-benzisothiazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1,2-benzisothiazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1,2-benzisothiazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisothiazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisothiazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzoxazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzoxazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzothiazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzothiazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1,3-benzothiazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1,3-benzothiazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo [2.2.2]oct-3-yl]-2-ethyl-1,3-benzothiazole-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-ethyl-1,3-benzothiazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1,3-benzodioxole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-ethyl-1,3-benzodioxole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2,2-dimethyl-1,3-benzodioxole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-benzofuran-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2H-isoindole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1H-benzimidazole-5-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl][1,3]thiazolo [5,4-c]pyridine-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl][1,3]thiazolo[4,5-c]pyridine-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl][1,3]dioxolo[4,5-c]pyridine-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[4,5-c]pyridine-6-carboxamide; N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1H-imidazo[4,5-c]pyridine-6-carboxamide; or a pharmaceutically acceptable salt thereof.    
     
     
         106 . The method of  claim 102 , wherein the compound of Formula I has the S stereochemistry at C3 of quinuclidine.  
     
     
         107 . The method of  claim 106 , wherein the compound of Formula I includes N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-6-carboxamide; N-((3S)1-azabicyclo [2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-6-carboxamide; N-((3S)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-5-carboxamide; N-((3S)1-azabicyclo [2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-5-carboxamide; N-((3S)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzothiazole-6-carboxamide; N-((3S)1-azabicyclo[2.2.2]oct-3-yl)indane-5-carboxamide; N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzodioxole-5-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[5,4-c]pyridine-6-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2-benzoisothiophene-5-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-5-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-6-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-5-carboxamide; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-6-carboxamide; or a pharmaceutically acceptable salt thereof.  
     
     
         108 . The method of  claim 99 , wherein the disease or condition is psychosis.  
     
     
         109 . The method of  claim 100 , wherein the disease or condition is psychosis.  
     
     
         110 . The method of  claim 101 , wherein the disease or condition is psychosis.  
     
     
         111 . The method of  claim 102 , wherein the disease or condition is psychosis.  
     
     
         112 . The method of  claim 103 , wherein the disease or condition is psychosis.  
     
     
         113 . The method of  claim 104 , wherein the disease or condition is psychosis.  
     
     
         114 . The method of  claim 105 , wherein the disease or condition is psychosis.  
     
     
         115 . The method of  claim 106 , wherein the disease or condition is psychosis.  
     
     
         116 . The method of  claim 107 , wherein the disease or condition is psychosis.  
     
     
         117 . The method of  claim 99 , wherein the disease or condition is attention deficit disorder, attention deficit hyperactivity disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, depression, general anxiety disorder, age-related macular degeneration, Parkinson's disease, tardive dyskinesia, Pick's disease, post traumatic stress disorder, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain  
     
     
         118 . The method of  claim 100 , wherein the disease or condition is attention deficit disorder, attention deficit hyperactivity disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, depression, general anxiety disorder, age-related macular degeneration, Parkinson's disease, tardive dyskinesia, Pick's disease, post traumatic stress disorder, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.  
     
     
         119 . The method of  claim 101 , wherein the disease or condition is attention deficit disorder, attention deficit hyperactivity disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, depression, general anxiety disorder, age-related macular degeneration, Parkinson's disease, tardive dyskinesia, Pick's disease, post traumatic stress disorder, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.  
     
     
         120 . The method of  claim 102 , wherein the disease or condition is attention deficit disorder, attention deficit hyperactivity disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, depression, general anxiety disorder, age-related macular degeneration, Parkinson's disease, tardive dyskinesia, Pick's disease, post traumatic stress disorder, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.  
     
     
         121 . The method of  claim 103 , wherein the disease or condition is attention deficit disorder, attention deficit hyperactivity disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, depression, general anxiety disorder, age-related macular degeneration, Parkinson's disease, tardive dyskinesia, Pick's disease, post traumatic stress disorder, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.  
     
     
         122 . The method of  claim 104 , wherein the disease or condition is attention deficit disorder, attention deficit hyperactivity disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, depression, general anxiety disorder, age-related macular degeneration, Parkinson's disease, tardive dyskinesia, Pick's disease, post traumatic stress disorder, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.  
     
     
         123 . The method of  claim 105 , wherein the disease or condition is attention deficit disorder, attention deficit hyperactivity disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, depression, general anxiety disorder, age-related macular degeneration, Parkinson's disease, tardive dyskinesia, Pick's disease, post traumatic stress disorder, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.  
     
     
         124 . The method of  claim 106 , wherein the disease or condition is attention deficit disorder, attention deficit hyperactivity disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, depression, general anxiety disorder, age-related macular degeneration, Parkinson's disease, tardive dyskinesia, Pick's disease, post traumatic stress disorder, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.  
     
     
         125 . The method of  claim 107 , wherein the disease or condition is attention deficit disorder, attention deficit hyperactivity disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down's syndrome, dementia associated with Lewy Bodies, Huntington's disease, depression, general anxiety disorder, age-related macular degeneration, Parkinson's disease, tardive dyskinesia, Pick's disease, post traumatic stress disorder, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.